Establishing the novel ex-vivo focal demyelination model of Multiple Sclerosis in other laboratories to reduce and replace live animal use.

目前用于治疗多发性硬化症（MS）患者的疗法不足以管理进行性MS，因此需要新的疗法。MS患者的中枢神经系统有一些区域似乎相对不受影响（神经元纤维保留其称为髓鞘的绝缘鞘），而其他区域受损（髓鞘丢失，损害神经元功能和健康）。这是一个动态的情况，身体不断修复损伤，但最终随着疾病的进展而失败。许多研究旨在增强髓鞘再生（修复髓鞘）作为新的治疗干预的关键领域，从而保护神经元的健康和功能。然而，为了测试新的基于髓鞘再生的疗法，必须使用实验室动物来模拟MS，并且这些模型昂贵，通常不能忠实地复制人类疾病的“斑片状”性质，并且对治疗如何起作用的解释有限。我们最近制作了一个更好的MS实验室模型，该模型允许MS脱髓鞘的这种斑片状性质在培养皿中重现，而无需在该过程中使用活体动物。研究人员现在可以第一次研究培养皿中“健康”和“受损”组织之间的复杂相互作用。这一进步意味着新的髓鞘再生疗法可以更快，更有效地进行测试，更好地了解它们是如何工作的，并大大减少了所需的动物数量。以前，一只成年动物会给出其神经系统的一个区域的一个实验结果（即，大脑或脊髓），我们的新模型使用了在培养皿中培养并单独分析的安乐死新生小鼠大脑或脊髓切片。这给了研究人员6个大脑切片和10个脊髓切片-所有这些都来自一只动物。在100只实验室动物将用于单一治疗测试的情况下，现在可以使用一些动物的组织来代替，并且还可以更好地了解治疗如何工作。同样值得一提的是，以前的实验动物可能不得不在创造MS条件所需的干预期间经历痛苦，而我们开发的这种新模型不对活体动物进行干预，从而取代了活体动物的使用。看到这种模型增加科学价值和减少动物使用的力量，我们现在很想把这些技术和知识传授给其他研究MS的研究小组。Dombrowski博士和Fitzgerald教授都在贝尔法斯特女王大学管理着独立的研究小组，他们与我们联系，希望在他们的实验室里使用这个模型。这笔赠款有三个目的。首先，资助一名研究人员将与新MS模型相关的技能和知识带到贝尔法斯特实验室。主要目的是通过用我们的新模型取代现有的活体动物模型，减少研究所需的动物数量。其次，我们的目标是通过在线免费提供培训视频和详细的协议，鼓励在英国，欧洲和其他地方广泛采用这种模式，从而提高MS研究能力，减少动物使用。最后，我们将优化制造这种新MS模型所需材料的生产，以便以简单，具有成本效益和可重复的方式轻松推广到大量实验室。我们预见这种新的多发性硬化模型将给研究人员带来直接和切实的好处，这将是促使他们采用它的主要吸引力。这些好处包括降低成本（活体动物实验成本高昂），同时在多个神经系统区域工作的能力，以及更好地了解治疗是如何工作的。需要这笔赠款来催化和推动这种采用，传播这种模式所需的知识和协议，减少全球范围内的动物使用。

Current therapies for treating multiple sclerosis (MS) patients are inadequate for managing progressive MS, so new therapies are needed. The central nervous system of MS patients has some areas that seem relatively unaffected (the neuronal fibres retain their insulating sheath called myelin), whereas other areas are damaged (the myelin is lost, compromising neuronal function and health). This is a dynamic situation, whereby the body continually repairs the damage, but ultimately fails with disease progression. Much research aims to enhance remyelination (repairing the myelin sheath) as a key area for new therapeutic intervention, thus protecting the health and function of the neurons. However, to test new remyelination based therapies, laboratory animals must be used to model MS, and these models are costly, often don't faithfully replicate the "patchy" nature of the human disease, and shed limited light on how the therapy worked.We have recently made a better laboratory model of MS, that allows this patchy nature of MS demyelination to be recapitulated in a dish, without using live animals in the process. Researchers can now, for the first time, study the complex interplay between the "healthy" and "damaged" tissue in a dish. This advancement means that new remyelination therapies can be tested faster, more effectively, with better understanding of how they are working, and greatly reduces the number of animals required.Where previously one live adult animal would give one experimental result for one region of their nervous system (i.e., either the brain or spinal cord), our new model uses slices of euthanised newborn mouse brain or spinal cord cultured in dishes and analysed separately. This gives researchers six brain slices AND 10 spinal cord slices - all from a single animal. Where 100s of lab animals would be used for a single therapeutic test, now the tissue of a few animals can be used instead, with the added benefit of better understanding how the therapy works too. It is also important to mention that previously an experimental animal may have had to experience suffering during the interventions required to create the MS condition, whereas no intervention is carried out on a live animal with this new model that we have developed, thus replacing the use of live animals.Having seen the power of this model to increase scientific value and reduce the use of animals, we are now keen to transfer these skills and knowledge to other research groups working on MS. Dr. Dombrowski and Prof. Fitzgerald, both running independent research groups at Queen's University Belfast, approached us to use this model in their laboratories. This grant has three aims. Firstly, to finance a researcher to bring the skills and knowledge associated with the new MS model to the Belfast laboratories. The primary aim is to reduce the number of animals needed in their research, by replacing their existing live animal models with our new model. Secondly, we aim to encourage widespread adoption of this model throughout the UK, Europe and elsewhere, by making training videos and detailed protocols freely available online, thus leading to better MS research capabilities with lower animal use. Lastly, we will optimise the production of the materials required to make this new MS model, so that it can easily be rolled out to large number of laboratories in a simple, cost-effective and reproducible manner. We foresee that the immediate and tangible benefits that this new model of MS will bring to researchers will be a major attraction driving them to adopt it. These include reduced costs (live animal experiments are costly), the ability to work on multiple nervous system regions concomitantly and gaining better insight into how the therapeutic is working. This grant is required to catalyse and drive this adoption, spreading the knowledge and protocols required for this model, reducing animal use worldwide.